JP2003523329A - Method for increasing arousal by administration of vomeroferin and alarm device for releasing vomeroferin - Google Patents

Abstract

A method of increasing alertness in an individual by administering an effective amount of an alertness-increasing vomeropherin to the individual; and an alarm device that, when activated, emits an alertness-increasing vomeropherin. The method and device are especially useful in increasing alertness in individuals who are not readily responsive to usual external stimuli.

Description

Detailed Description of the Invention

FIELD OF THE INVENTION The present invention relates to a method of increasing alertness in an individual by administering to the individual an effective amount of vomeroferin that increases alertness, and releasing vomeroferin that increases alertness when activated. Alarm device. The method and device are particularly useful for increasing alertness in individuals who do not readily respond to external stimuli.

BACKGROUND INFORMATION Fire and smoke alarms are designed to alert building occupants of a fire. In recent years, they have been considered essential life-saving devices and have become a standard feature of most homes and commercial buildings. Most home fire alarms on the market today produce an audible signal to alert and / or recognize individuals in the vicinity of a fire that has occurred. Some fire alarms produce a visible signal, for example a flashing one.

Carbon monoxide alarms are designed to alert a building occupant of carbon monoxide gas in the atmosphere of the building. Carbon monoxide is a product of incomplete combustion, which cannot be detected by individuals (the gas is colorless and odorless),
These are becoming more common with respect to home use, for example because they can arise from fires or, more commonly, from malfunctioning gas appliances such as furnaces. These alarms also typically produce an audible signal and may produce a visible signal.

Alarms also include, but are not limited to, radon (tasteless, odorless, and invisible gas), propane gas, methane, apnea (breath arrest), or trespassing (for residential intruder alarms). It may also be used to indicate the presence of other alarm conditions, including presence.

The alarm also rings an alarm condition (in a situation that is generally non-hazardous), such as a telephone call (a request for the individual to answer the phone), a buzzer or a bell, where there is a request for the individual to respond. It may also be used to indicate the presence of an alarm clock (a request for the individual to wake up), a doorbell call (a request for the individual to answer the door), etc.

However, normally due to sleep disorders, due to drug- or alcohol-induced drowsiness, or due to symptoms such as anolence (lack of smell), hearing damage, or blindness, For individuals prone to deep sleep, normal stimuli (direct danger-related stimuli, such as the presence of smoke, or stimuli from alarm systems) alert them to alarm conditions and allow them to take appropriate action. Would not be effective in

Therefore, it is desirable to develop a method of increasing alertness in an individual. Also,
It would be desirable to develop an alarm device that would increase an individual's alertness in the presence of an alarm condition and allow the individual to respond more effectively to that alarm condition.

SUMMARY OF THE INVENTION In a first aspect, the invention is a method of increasing wakefulness in an individual, wherein an effective amount of a formula that increases wakefulness in the vomeronasal organ (VNO) of the individual:

[Chemical 6] [Wherein R ₁ is hydrogen, C _1-5 alkanoyl, or —SO ₃ H or a salt thereof, R ₂ is hydrogen or methylene; R ₃ is hydrogen or C _1-4 alkyl; , 1 or 2 non-adjacent members of "b", "c", and "d" are optionally double bonds; and when R ₂ is hydrogen, "e" is a double bond or 16α. , 17α-epoxide, and when R ₂ is methylene, “e” is absent and “f” is a double bond]
There is provided a method comprising administering a compound represented by:

In a second aspect, the present invention is an alarm device for alerting an individual to the presence of an alarm condition, comprising: (a) a detector for the presence of an alarm condition; An effective amount formula for increasing arousal in the vomeronasal organ:

[Chemical 7] [Wherein R ₁ is hydrogen, C _1-5 alkanoyl, or —SO ₃ H or a salt thereof, R ₂ is hydrogen or methylene; R ₃ is hydrogen or C _1-4 alkyl; , 1 or 2 non-adjacent members of "b", "c", and "d" are optionally double bonds; and when R ₂ is hydrogen, "e" is a double bond or 16α. , 17α-epoxide, and when R ₂ is methylene, “e” is absent and “f” is a double bond]
A dispenser for administering a compound represented by: and optionally (c) a device comprising a warning means.

DETAILED DESCRIPTION OF THE INVENTION Definitions Unless otherwise stated, the following terms used in the specification and claims have the meanings given below.

“Awakening” includes recognition and reaction to external stimuli. Therefore, "increasing arousal in an individual" refers to recognizing the individual for effects that may occur by illuminating an external stimulus, a sleep state, but without complete awakening, as well as increasing the individual's response. Either or both are included. Thus, increasing arousal in an individual means increasing the individual's response to external stimuli such as ringing a bell, ringing a phone, fire, smoke and the like. This individual is
It can be an individual who has no medical condition that impairs alertness, eg, a healthy individual. Alternatively, the individual may have the following symptoms: 1) symptoms of impaired arousal of the individual, such as individuals who have taken hypnotics; and / or 2) individuals who have the disease. , A condition in which the health of the individual is impaired.

An “alarm condition” with respect to an individual is a condition in which the individual or other safety or health can be adversely affected by a lack of response by the individual, or a condition in which the individual is required to respond. . Examples of alarm situations in which the individual or other safety or health may be adversely affected by lack of response by the individual include fire, smoke,
This includes poisonous gases (eg carbon monoxide), trespassing (eg into private homes), etc. Examples of other safety or health conditions that can be adversely affected by a lack of response include the conditions listed above and other conditions, such as apnea (e.g. for sleeping infants-such as Baby monitors that warn parents of an outbreak are commercially available). It also indicates that chronically ill humans (eg, those with lung or cardiovascular disease) require immediate rescue, especially in home health settings where responding individuals have not been up all night. There are certain situations and situations in which rescue may be requested using a “call buzzer” or the like. Examples of alarm situations (in general non-hazardous situations) in which an individual is required to respond include: buzzer alarm clock (request to wake up individual), phone call (request to answer phone), doorbell. Call (request to answer the door) and so on. Therefore, an "alarm" or "alarm" for such alarm situations
An "alarm device" includes not only an alarm whose alarm condition may be detected by the detection of a condition in which the individual or other safety or health may be adversely affected by the lack of response by the individual, as well as the response by the individual. Detecting situations that are required to be included.

“C _1-4 alkyl” means a cyclic, branched, or straight-chain monovalent hydrocarbon group having 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, 2-propyl,
Represents cyclopropyl, butyl, 2-butyl, 2-methylpropyl, 1,1-dimethylethyl, and cyclopropylmethyl.

[0014]   "C_1-5"Alkanoyl" refers to the group: -C (O) -R, where R is hydrogen or C _1-4 Is alkyl).

[0015]   "Effective amount" refers to an amount sufficient to increase alertness in an individual.

“Vomeroferrin” is a compound that functions as a chemosensitive messenger and binds to specific vomeronasal neuroepithelial receptors to induce physiological or behavioral effects. The action of "bomeroferrin" is mediated by its interaction with the vomeronasal organ (VNO).

The varying term “comprising” is an open-ended term synonymous with “including” and does not exclude additional, unlisted elements.

[0018] Vomeroferin   Vomeroferin that increases alertness that can be used in the present invention has the formula:

[Chemical 8] [Wherein R ₁ is hydrogen, C _1-5 alkanoyl, or —SO ₃ H or a salt thereof; R ₂ is hydrogen or methylene; R ₃ is hydrogen or C _1-4 alkyl; , 1 or 2 non-adjacent members of "b", "c", and "d" are optionally double bonds; and when R ₂ is hydrogen, "e" is a double bond or 16α. , 17α-epoxide, and R ₂ is methylene, “e” is absent and “f” is a double bond]
Is a compound represented by.

The 13th position of these compounds is a chiral center and 13-methyl has the β configuration. When both “a” and “b” are absent and R ₃ is C _1-4 alkyl, the 7-position is also a chiral center and the 7-alkyl is in the α configuration.

A preferred vomeroferrin is where R ₁ is acetyl, R ₂ and R ₃ are hydrogen, “a”, “b”, “c” and “d” are absent and “e” is divalent. A compound represented by the above formula which is a heavy bond, that is, estra-1,3,5 (10), 16-
It is tetraen-3-yl acetate.

Another preferred vomeroferin is R ₁ is hydrogen and R ₂ is methylene,
R ₃ is absent, “a”, “c” and “f” are present, “b” and “d”
Is absent, i.e., 17-methylene-1,3,5 (
10), 6,8-Pentaen-3-ol.

Vomeroferin useful in the present invention can be prepared according to general procedures for steroid synthesis well known to those skilled in the art (eg Fieser, LF).
and M. Fieser, Steroids, Reinhold, New York, 1959). Specific reaction conditions can be mechanically determined by experiments.

For example, estra-1,3,5 (10), 16-tetraen-3-ol is an estrone (estra-1,3,5 (10)) under reflux in a polar solvent such as dry methanol or ethanol. -Trien-3-ol-17-one) in an appropriate amount of p-
It can be prepared by reacting with toluenesulfonyl hydrazide to form the corresponding estrone p-toluenesulfonylhydrazone. Estrone p-toluenesulfonylhydrazone is then added to an inert aprotic solvent,
For example, by reacting with n-butyllithium in dry tetrahydrofuran, ether, dimethoxyethane, etc., estra-1,3,5 (10), 16-tetraene-3
-Manufacture oars.

Prepared by acylation of the acyl derivative of estra-1,3,5 (10), 16-tetraen-3-ol by conventional means, for example by treatment with the appropriate anhydride in ether / pyridine at room temperature. .

A compound of the formula where R ₂ is hydrogen and “e” is 16α, 17α-epoxide can be prepared according to the method set forth in Example 3 below.

Salts of compounds where R ₁ is —SO ₃ H may include metal salts such as sodium salts, potassium salts, lithium salts and the like. The procedure for salt synthesis is illustrated in Example 4 below. The salt derivative has an advantage that it can be easily crystallized and easily solubilized.

Purification of the product can be achieved by chromatographic and / or crystallization means known to those skilled in the art.

These bomeroferins have psychostimulatory effects, including primary wakefulness, which reduces total sleep time and sleep onset latency.
ncy). These are also external stimuli such as fire, smoke,
Increases an individual's alertness (cognition) to stimuli with the presence of alarm conditions such as audible or visual alarms.

They have the effect of increasing alertness in normal individuals; however, they are normally associated with sleep disorders, drug- or alcohol-induced sleepiness,
Or having an olfaction (lack of olfaction), hearing damage, or a blindness-like symptom, tending to sleep deeply, resulting in a decreased response to stimuli, especially normal stimuli with dangerous situations It is expected to be particularly useful in individuals.

Administration and Delivery 1) Vomeronasal Organ (VNO) The present invention involves the non-systemic delivery of vomeroferin to VNO that increases alertness. Delivery provides contact of neurochemoreceptors in VNOs, known as Jacobson's organs, with such vomeroferrin. VNOs are small, bilateral nasal organs with a central lumen and a hole that opens into the nasal cavity. This lumen is lined with sensory neuroepithelium and constitutes a distinct location for chemosensitive receptors. The chemosensitive cells of the VNO neuroepithelium form the vomeronasal nerve and have direct inputs to the basal tonsillar and hypothalamic nuclei inside the cortex of the brain. Also, the distal axons of terminalis neurones can act as neurochemoreceptors in VNO.

[0031]   2) Composition and method of delivery   The vomeroferin of the present invention is administered to an individual via release into the environment.

These vomeroferin should be released into the environment by an aerosol dispenser, which is intended for spraying into large enclosed areas, with a propellant gas for delivery as a fine spray or mist. You can A typical dispenser contains a suspension or solution of vomeroferrin mixed with a liquefied gas propellant or a mixture of water, ethanol and propellant. The propellant may be one or more gases, such as chlorofluorocarbon (CFC), or other non-toxic, non-flammable, non-CFC gas. This propellant must be volatile so that it evaporates when released into the air, leaving only vomeroferrin, which increases alertness. It is also possible to use an aerosol dispenser in a compartment where the unliquefied pressurized gas propellant is separated from the aerosol solution (including vomeroferrin). Examples of possible propellants include nitrogen, carbon dioxide, nitrous oxide.

When delivered via the use of an aerosol, the compound exists in fine singularly divided form, unless dissolved. Typical percentages of compounds present in an aerosol composition are 0.001 to 2% by weight, preferably 0.
． It is 004 to 0.10%.

The aerosol composition may also include a surfactant. Suitable surfactants, of course, must be non-toxic and are preferably soluble in the propellant. Examples of such surfactants are aliphatic polyhydric acids containing from 6 to 22 carbon atoms, such as caproic acid, octanoic acid, lauric acid, palmitic acid, stearic acid, linoleic acid, eleostearic acid and oleic acid. Hydric alcohols or their cyclic anhydrides, such as ethylene glycol, glycerol, erythritol, arabitol, mannitol, sorbitol and hexitol anhydrides derived from sorbitol (sorbitan esters marketed under the trademark "Spans"), or partial esters; And polyoxyethylene and polyoxypropylene derivatives of these esters. Mixed esters, such as mixed or natural glycerides, can also be used. Preferred surfactants are sorbitan oleate, eg "Arlacel C" (sorbitan sesquioleate), "Span 80" (
Sorbitan monooleate) and "Span 85" (Sorbitan trioleate)
Is marketed as. The surfactant may make up 0.1 to 20% by weight of the composition, preferably 0.25 to 5%.

In making an aerosol, a container equipped with a suitable valve is filled with a suitable propellant, finely divided compound and optionally a surfactant. The ingredients are maintained under pressure until released.

When vomeroferrin is delivered as a vapor, this means of delivery is well known to those skilled in the field of neurophysiology (eg, Tucker, D. and T. Shibuya, C.
old Spring Harbor Symp. Quant. Biol. (1965) 30: 207 and Vigouroux, M.
et al, (J. Neurosci. Methods (1988) 24:57)).

In its basic form, the vapor delivery means is a source of constant air flow bubbled through a liquid medium. These vomeroferins may also be impregnated (preferably in a 1/30 weight ratio) into a material, eg sponge or cotton, in dry powder or crystalline form for delivery as a vapor. The vapor can be controlled in a single parameter or in combination with, for example, purity, temperature, water vapor pressure, flow rate, etc. Various stimulants, such as odorants, fragrances, drugs, etc., can be introduced into the vapor stream either continuously or, preferably, as pulses of a specified time. The crystals delivered must be of a single size without large lumps.

These vomeroferin can also be formulated in liquid compositions, for example, solutions that are sprayed into the environment. In this case, various non-toxic, non-flammable solvents or solvent mixtures which are able to dissolve vomeroferrin are suitable, for example ethanol, propylene glycol and DMSO (dimethyl sulfoxide). Generally, aqueous ethanol solvents are preferred. The preferred ethanol concentration in the mixture is in the range of 1-4% (v / v). However, since this solution is not administered directly to the nasal cavity, aqueous ethanol solvents with higher concentrations of ethanol would also be acceptable.

The concentration of vomeroferrin in the composition can vary. However, it must be of sufficiently high concentration to deliver an effective amount of the compound to an individual when released into the environment.

3) Effective Dose The vomeroferin of the present invention is effective in increasing alertness in both men and women, although there may be sexual differences in the doses at which this compound is effective. The range is 0.1 ng / 100 μL to 100 μg / 100 μL. VNO
A single dose of at least about 200 picograms delivered directly to the lumen of is effective in eliciting a transient autonomic nervous system response. When administered nasally, the dose will be from about 100 picograms to about 100 micrograms, preferably from about 1 nanogram.
It is about 10 micrograms, more preferably about 10 nanograms to about 1 microgram.

The doses are as described above when administered directly to the VNO or nose of the individual by the device. However, when a dose is administered to provide a sufficient concentration of vomeroferin in the air around the individual and contacts the VNO of the individual by inhalation through the nose or intranasal application, it is diffused to achieve that dose. The amount of vomeroferin should be substantially higher, depending on such factors as the number of individuals awakened, the number of individuals in the room, the size of the room, and the position of the dispenser.

For example, assuming that a human at rest exchanges an average of 4 liters of air per minute, a dispenser containing 100 mg of vomeroferrin is 25 cubic meters,
Capacity of approximately 9 ft. × 12 ft × 8 ft room volume; a dispenser containing 8 mg of vomeroferrin fills a 2 cubic meter volume (eg when this dispenser is mounted on a bed board) Is enough for If the room has a continuous air flow, the loss of vomeroferin in the air is negligible.

Accordingly, one of ordinary skill in the art, with their skill and this disclosure, will be able to calculate the appropriate total amount required to achieve an effective amount for increasing alertness in an individual.

Alarm Devices Typical alarm devices (for hazardous and non-hazardous situations) are limited to the presence of alarm conditions (eg, fire, smoke, trespass, or need to answer the phone). Detector), and a warning means for generating one or more alarm signals, such as a horn or a glowing light. For example, smoke alarm detectors sense the presence of smoke by photoelectron or ionizing means. When the detector senses the presence of smoke, an electronic signal is sent to the acoustic assist relay to activate a warning means, such as a horn, to generate an alarm signal.

There are typically two types of smoke alarms. The ionizing smoke alarm consists of two plates and uses an ionizing compartment with a potential difference across it, together with a radioactive source of ionizing radiation, typically a very small amount of Americium-241. This detector works by measuring the change in ionization caused by smoke entering the compartment.

The optoelectronic smoke alarm, on the other hand, uses lights and photodetectors to detect a fire outbreak. Under normal conditions, the light from the light source crosses straight and leaves the detector. However, smoke particles scatter light, resulting in a small amount of light striking the detector and activating an alerting means, such as a horn.

The detector in the carbon monoxide (CO) alarm measures CO levels over time. This includes more CO in a short period or less C in a longer time frame.
There can be O. In either case, when the detector senses a constant saturation level of CO, an electronic signal is sent and the horn is triggered.

Detectors of alarm devices, such as, but not limited to, smoke, carbon monoxide, trespass, telephone connections, or doorbell detectors, containing detectors for sensing alarm conditions and vomeroferin for increasing alertness It is possible to create the alarm device of the present invention that is composed of a dispenser that A warning means for producing an audible and / or visible signal,
For example, a horn or light may be incorporated into the alarm device.

The dispenser can be contained within or outside the alarm device. In practice, it is preferred that the dispenser be placed in a position that is close to the individual, for example near the individual's bed, so that vomeroferrin is more easily received by the individual.

[0050] In either case, when the detector senses an alarm condition, the dispenser is activated to release vomeroferin, which increases alertness, which increases alertness in the individual. If other alerting means are present, they also work.

[0051]   The invention is illustrated by the following examples.

Example 1 Synthesis of estra-1,3,5 (10), 16-tetraen-3-ol Estrone p-toluenesulfonylhydrazone Estrone (270 g, 1.00 mo) in dry methanol (2.5 liters).
1) and p-toluenesulfonyl hydrazide (232.8 g, 1.25 mol)
Was heated to reflux for 20 hours. The mixture was transferred to a conical flask and allowed to cool. The crystalline product was filtered off under suction and washed with methanol (300 mL). The filtrate,
Further amounts of product were obtained by continuous evaporation to 2000 mL, 800 mL and 400 mL and crystallizing at each time point. Total yield is 433
． It was 5 g (99%).

1,3,5 (10), 16-Estratetraen-3-ol Estrone p-toluenesulfonylhydrazone (219.0 g, 500 mmol) in dry tetrahydrofuran (8.0 L) was added to a sodium chloride / ice bath. Cooled in. While mechanically stirring the mixture, n-butyllithium (800 mL of a 2.5 M solution in hexane, 2.00 mol) was added with a double-ended needle. The mixture was stirred at room temperature for 3 days. Ice (250 g) was added, followed by saturated ammonium chloride solution (500 mL). After stirring to mix the phases, they were allowed to stand. The aqueous phase was removed by suction using a Teflon tube, ether (500 m
L). Two organic phases were combined with saturated sodium bicarbonate solution (500 mL) in the same bath.
Then washed successively with saturated sodium chloride solution (500 mL). The organic layer was dried (MgSO _4), evaporated under reduced pressure to give the crude product. This is 50
Flash filtration over 0 g silica gel 60, 230-400 mesh (eluting with ethyl acetate / hexane (25:75, 2.5 liters)). The filtrate was evaporated under reduced pressure to give a crystalline material. The product is methanol (300 mL) / water (75 m
It was recrystallized from L) and washed with methanol (80 mL) / water (20 mL). Further recrystallization from ethyl acetate / hexane (12.5: 87.5) gave pure product (
88.9 g, 70%) was obtained.

Example 2 Synthesis of Estra-1,3,5 (10), 16-tetraen-3-ol-acetate 1,3,5 (10), 16-Estratetraene-in ether (10 mL)
Acetic anhydride (0.25 mL) was added to 3-ol (254 mg, 1.00 mmol), followed by pyridine (0.25 mL), and the mixture was stirred at room temperature for 16 hours. The mixture was poured onto ice / water and extracted with ether (2 x 20 mL). The organic extract is washed with water, saturated copper sulphate solution, water and saturated sodium chloride solution and dried (MgS
O ₄₎ and evaporated under reduced pressure to give the crude material. This was flash chromatographed (10%) on 17.5 g silica gel 60 (230-400 mesh).
Purified by eluting with -12% ethyl acetate / hexane) to give pure product (192
mg, 65%). Other esters can be made with the appropriate anhydride.

[0055] Example 3 estra-1,3,5 (10), 16-tetraene-3-ol - Synthesis of acetate et Pokishido 1,2-dimethoxyethane (DME) in 25mL of 3-chloroperoxybenzoic acid ( 862.9 mg, 5.000 mmol) to Estra-1 in 15 mL DME.
, 3,5 (10), 16-tetraen-3-ol (636.0 mg, 2.500)
mmol) solution. After stirring for 6 hours, the reaction mixture was poured into 140 g of 5% (w / w) sodium thiosulfate pentahydrate and extracted into 3 × 100 mL of ethyl acetate. The extracts are combined, 100 mL saturated sodium bicarbonate and 3 × 100 brine.
Wash with mL, dry over magnesium sulfate, and filter through Celite 503.
The residue was washed with 50 mL of ethyl acetate, the filtrates were combined and concentrated under reduced pressure. The residue was subjected to flash chromatography (20% ethyl acetate / hexanes on silica gel) then crystallized from ethyl acetate to give shiny white platelets (349.9m).
g, 1.294mmole, 52%). Mp 217-219 [deg.] C, TLC (20% ethyl acetate / hexane on silica gel; _Rf 0.32; starting material _Rf 0.50).
Same quality as.

Acetic anhydride (0.70 mL, 7.0 mL) was added to a suspension of the material (400.0 mg, 1.479 mmol) prepared by the above procedure in anhydrous pyridine (2.4 mL, 30 mmol).
4 mmol) was added. After stirring for 18 hours, methyl t-butyl ether (MTB
E, 15 mL) was added and the reaction mixture was treated with 1N HCl (3 × 5 mL) and saturated copper sulfate (5 m).
L, washed with 5 mL saturated sodium bicarbonate, and 5 mL brine, dried over magnesium sulfate, and filtered through Celite 503. The residue was washed with 5 mL MTBE and the combined filtrate was concentrated under reduced pressure. The residue was recrystallized from 95% ethyl acetate using a charcoal mediated treatment to give fine white platelets (295.1 mg, 0.9446).
mmole, 64%) was obtained. Melting point 114-115 ° C, TLC (20% on silica gel
Ethyl acetate / hexane; R _f 0.36; same quality as the starting material R _f 0.24).

[0057] Example 4 estra-1,3,5 (10), 16-tetraene-3-yl synthesis of sulfur trioxide / pyridine complex sulfates potassium salt (3.8 g, 23.9 mmol), dry dimethyl Estra-1,3,5 (10) in 10 mL of formamide (stored on a molecular sieve),
Added to 16-tetraen-3-ol (1.00 g, 5.93 mmol). After stirring for 4 hours, the suspension was added dropwise with rapid stirring to triethanolamine (11.73 g, 78.62 mmol) in 200 mL of water and the resulting solution was filtered through a coarse glass frit. The filtrate is potassium carbonate (7.00 g, in 20 mL of water,
50.6 mmol) with rapid stirring and filtered through a coarse glass frit. The residue was washed with water (10 mL) and dried under reduced pressure with P ₂ O ₅ to give a solid (1.37 g, 3.68 mmol, 94% yield). Melting point 210-215 [deg.] C (decomposition).

Example 5 The following sleep was evaluated using three methods: 1) sleep studies, 2) quantitative electroencephalography, and 3) psychometric tests. This study was a randomized, single-blind,
A placebo-controlled experimental design was used.

1. Participant selection and preparatory screening was done several days before the experimental session by clinical interviews and trials. In addition, the Hamilton A and D, and Covy tests were performed to measure associated anxiety or emotional disorders. In addition, a detailed questionnaire regarding sleep habits and sleep pathology was conducted for each subject. The criteria for participating in this study are Covy
Exam score of 12 or less and Hamilton A and Hamilton D
Subjects with a score of 8 or less in the study without any medical or psychiatric symptoms were included. Ten physically and mentally healthy young male adult subjects were selected for this study. All of them were normal sleepers (ie they fell asleep at night, reported no difficulty maintaining it, slept 6-8.5 hours per night, awakened during the day). did).

On the day of the study, they were instructed to stay asleep, avoid the consumption of alcohol or caffeine in their drinks, and maintain a certain level of daily vitality. Ten subjects were divided into two groups of five, the test compound was administered to one group, the other group served as a control.

2. Preparation of test compounds Test compounds were administered to VNOs using a manual vomeronasal applicator (MVA). This applicator delivers an air supply delivering 1 mL pulse of air;
The air pulse was applied to the test compound in ethanol, estra-1,3,5 (10),
A valve system that either pre-soaked in 1 mL of a 1 mg / mL solution of 16-tetraen-3-yl acetate and passed through or bypassed the compartment containing 30 mg of USP cotton that had been dried overnight; one-way flow valve. And a nozzle providing direct administration to the VNO lumen, which can be located in the nostril.
Using a 1 mL air pulse, MVA delivers 200 pg of test compound to VNO.

3. During sleep polygraphy and VNO stimulation studies, subjects spent overnight in a sleep laboratory and received conventional polysomnography (PSG) for the first hour. The criteria for this short-term recording was based on previous findings showing that a single dose of VNO stimulation with vomeroferrin induced an effect within 1 hour of stimulation. Prior to the start of recording, each subject was asked about fatigued or debilitated events of the day, which could contribute to sleep disruption. The time of the last meal and exercise (if applicable) was also recorded. Judgment and motor skills were also evaluated before going to sleep and in the morning to determine if the compounds affected daytime behavior or antegrade memory. For this purpose, the subjects were tested in the previous literature (Monti, JM, 1989, Slow Wave Sleep in Hea
lth and Disease. In: Waukier A., Dugovic C. and Radulovacki M. "Slow Wav
e Sleep. "New York, Raven Press. pp. 331-322), a maze test,
A digit-symbol substitution test, right and left manual adjustment tests (dot test) and digit repeat test were taken.

Immediately before “lighting off”, the subject was instructed to lie on his back. The MVA was placed in the right nostril and the nozzle was aimed at the right VNO opening. Then MVA was placed in the left nostril for stimulation of the left VNO. Two pulses of air or test compound or placebo were administered to each VNO. The procedure was repeated 30 minutes later, at which point the investigator entered the room and woke up if the subjects were asleep, ensuring that the total dose of vomeroferin administered to each subject was 800 pg.

At each 30 minute sleep break, prior to application of the test compound, each subject was given a short questionnaire to determine whether he was asleep, how long he spent sleepless, and how many times he woke up. Recognition was recorded. Further, sleepiness was measured by creating an analog scale list of 3 items (a score of 0 to 10, with higher numbers indicating higher sleepiness). This included a) ease of reversion to sleep; b) degree of anxiety and c) self-rated level of drowsiness. This scale displays diametrically opposite states at the ends of the horizontal lines, which include "complete awakening-complete sleep", "extreme restlessness-extremely restlessness", and "wanna sleep but not feel so". -"It is very easy to get back to sleep." Recording started at 10:00 pm and continued until 6:00 am the next day. Forehead, parietal and occipital electroencephalography (EEG), electrooculogram, and electromyography were recorded for the first hour. These records were coded and scored for non-REM sleep latency from "light out" to the first appearance of Stage I sleep, total time awake, time awake after sleep onset, and total sleep time. It was a blind. Sleep stage is Rechtsc
Assigned according to the criteria of haffen and Kales (1968). All variables were scored separately at each 30 minute interval. The number of wakeups was recorded during the entire recording time.

In the morning, all subjects completed a multi-choice questionnaire on the following variables: sleep latency, sleep estimation time, number of wakes, and sleep quality since last entry. Global status at the time of waking was measured by marking an analog scale of 9 items. In addition, all subjects underwent the same cognitive and motor performance tests that they received at bedtime.

4. Sleep Parameter Scores The sleep variables evaluated in this study included total sleep time (TST) or sleep volume during the recording time, sleep efficiency (SE) or percentage of sleep, sleep onset latency (SOL), or post-recording start. It included the time to fall asleep. Sleep was summed at the time Stage 1 sleep was first completed. Non-REM sleep was scored by the appearance of stages 1, 2, 3 and 4 and REM sleep was scored by the appearance of asynchronous EEG patterns, eye movements and flat muscle tone. The latency of each of these stages was also measured using a specific test of REM sleep latency. The length of each stage was also measured and expressed as a percentage of total sleep time (length of each sleep stage divided by total sleep time, multiplied by 100). Each subject also reported their sleep experience by answering a short questionnaire and a visual analog scale.

5. Test results A. Evaluation by sleep polygraphy The PSG results are summarized in Table 1. This is because the test group has a longer SO than the control group.
L, shorter TST, and shorter wake time after sleep onset. The SOL for the control group was 16 minutes and the test group was 21 minutes. The TST for the control group was 26 minutes and the test group was 14.3 minutes. S
Statistical significance P <0.05 is obtained for OL and TST.

B. Subject assessment a) Subject assessment-self-assessment at half-hour intervals The control group reported a sleep latency of 10 minutes or longer with varying numbers of wakes between subjects ranging from 0 to 3 or more. The study group reported sleep latencies ranging from 10 to 30 minutes with three or more wakeups.

B) Subject Evaluation-Self-Awareness of Drowsiness The results are summarized in Table II. This describes the score on the Drowsiness Scale list. At the start of the study, the test group showed no significant change from the control group. After administration, the control group reported decreased sleepiness.

C) Sleep Latency As shown in Table III, the control group had a sleep latency of less than 30 minutes, while the test group reported a latency of 30 minutes or longer.

D) Sleep time As shown in Table IV, the test group reported total sleep time in the range of 4-6 hours, while the control group reported sleep in the range of 7-8 hours. .

E) Sleep Quality Sleep quality was classified by the subject as either “disordered” or “undisturbed”. Most subjects reported that their sleep was "undisturbed." However, one subject in the test group made it clear that his sleep was "disturbed".

F) Morning Wake State The response to the patient's state at the time of waking was labeled as "calm and refreshing", "tired" or "sleepy". In their answer, regardless of treatment modality,
Everyone wrote "calm and refreshing" or "tired." Morning conditions assessed by the visual analog scale did not show any difference between placebo- or test compound-treated groups.

G) Motor skill recognition test Neither the control group nor the test group showed any change in scores between the night and morning tests for antegrade memory, judgment or dexterity of exercise.

6. Conclusions The test compound, estra-1,3,5 (10), 16-tetraen-3-yl acetate, has been shown to have a primary arousal effect as demonstrated by a decrease in TST. A correlation of sleep latency between recordings and self-reported responses is evident in subjects treated with the test compound. One subject reported poor sleep, which corresponds to a short total sleep time in PSG.

The control group reported similar results both in subject assessment and PSG results. Self-reported sleepiness on an analog scale during the study was consistent with PSG data. The above data appear to indicate that the test compound does not impair the patient's sleep self-awareness. This claim is further supported by the lack of change in cognitive tests before and after treatment.

In the morning trial, the test group reported a sleep latency of more than 30 minutes after VNO stimulation, which was in contrast to the control group, which was shown to fall asleep within 30 minutes. The test group also reported spending less sleep time compared to the control group. Summarizing the PSG data from the test groups, the above significant results seem to indicate a potential psychostimulant effect of the test compounds.

Table I Effects assessed by polysomnography in human subjects treated with estra-1,3,5 (10), 16-tetraen-3-yl acetate and placebo.

[Table 1]

Table II Self-awareness of drowsiness in human subjects treated with estra-1,3,5 (10), 16-tetraen-3-yl acetate and placebo

[Table 2]

[0080] Table III Sleep latency

[Table 3]

[0081] Table IV time of sleeping

[Table 4]

Although the present invention has been described in terms of its specific embodiments, those skilled in the art will appreciate that various changes can be made and substituted with equivalents without departing from the true spirit and scope of the invention. Should be. In addition, many modifications may be made to adapt a particular composition or device to a particular subject of the invention. All such modifications are intended to be within the scope of the claims.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) C07J 71/00 C07J 71/00 G08B 21/02 G08B 21/02 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM , AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, A, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP , KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, R O, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Lewis Monty United States 84108 Utah East Nottingham Way # 2646 (72), Salt Lake City, U.S.A. Inventor Clive El Jennings-White United States 84019 South Lake 2300 East 3096 F Term, Salt Lake City, Utah (reference) Four C086 AA01 AA02 DA09 DA12 MA01 MA04 MA12 MA13 MA59 ZA11 ZA12 ZC42 4C091 AA02 BB01 BB04 BB07 BB11 CC01 DD01 EE03 EE05 FF01 GG01 HH01 JJ01 KK01 QL01 QC01 Q20Q20QQQQQQQQQQQQQQQQQ01

Claims (21)

[Claims] 1. A method of increasing alertness in an individual, the formula of an effective amount for the vomeronasal organ of the individual: [Wherein R ₁ is hydrogen, C _1-5 alkanoyl, or —SO ₃ H or a salt thereof; R ₂ is hydrogen or methylene; R ₃ is hydrogen or C _1-4 alkyl; , 1 or 2 non-adjacent members of "b", "c", and "d" are optionally double bonds; and when R ₂ is hydrogen, "e" is a double bond or 16α. , 17α-epoxide, and when R ₂ is methylene, “e” is absent and “f” is a double bond]
A method comprising administering a compound represented by: 2. The method of claim 1, wherein the administering comprises releasing the compound into the environment around the individual.
The method described in. 3. R ₁ is acetyl, R ₂ and R ₃ are hydrogen, and “a
, "B", "c" and "d" are absent, and "e" is a double bond, ie the compound is estra-1,3,5 (10), 16-tetraene-3-
The method according to claim 1, which is isopropyl acetate. 4. The method of claim 1, wherein increased alertness is manifested by increased response to external stimuli, including alarm signals. 5. An alarm device for alerting an individual to the presence of an alarm condition, comprising: (a) a detector for the presence of an alarm condition; and (b) increasing arousal in the vomeronasal organ of the individual. Formula of effective dose: [Wherein R ₁ is hydrogen, C _1-5 alkanoyl, or —SO ₃ H or a salt thereof; R ₂ is hydrogen or methylene; R ₃ is hydrogen or C _1-4 alkyl; , 1 or 2 non-adjacent members of "b", "c", and "d" are optionally double bonds; and when R ₂ is hydrogen, "e" is a double bond or 16α. , 17α-epoxide, and when R ₂ is methylene, “e” is absent and “f” is a double bond]
A device comprising a dispenser for administering a compound represented by: 6. The alarm device of claim 5, wherein the dispenser releases the compound into the environment around the individual. 7. R ₁ is acetyl, R ₂ and R ₃ are hydrogen, and “a
, “B”, “c” and “d” are absent and “e” is a double bond, ie the compound is estra-1,3,5 (10), 16-tetraen-3-yl The alarm device according to claim 5, which is acetate. 8. The alarm device of claim 5, wherein the detected alarm condition is the presence of a fire, carbon monoxide, methane, propane, radon or trespass. 9. The alarm device according to claim 5, wherein the individual is an apnea individual. 10. Alarm device according to any of claims 5 to 9, further comprising warning means for producing an audible and / or visible signal. 11. The formula: embedded image [Wherein R ₁ is hydrogen, C _1-5 alkanoyl, or —SO ₃ H or a salt thereof; R ₂ is hydrogen or methylene; R ₃ is hydrogen or C _1-4 alkyl; , 1 or 2 non-adjacent members of "b", "c", and "d" are optionally double bonds; and when R ₂ is hydrogen, "e" is a double bond or 16α. , 17α-epoxide, and when R ₂ is methylene, “e” is absent and “f” is a double bond]
A composition for increasing arousal in an individual via the vomeronasal organ of the individual, comprising a compound represented by the formula: 12. R ₁ is acetyl, R ₂ and R ₃ are hydrogen, and
a "," b "," c "and" d "are absent," e "is a double bond,
That is, the compound is estra-1,3,5 (10), 16-tetraen-3-yl
The composition of claim 11, which is acetate. 13. The composition of claim 11, wherein increased alertness is manifested by increased response to external stimuli, including alarm signals. 14. In the manufacture of a composition for increasing arousal in an individual, the formula: [Wherein R ₁ is hydrogen, C _1-5 alkanoyl, or —SO ₃ H or a salt thereof; R ₂ is hydrogen or methylene; R ₃ is hydrogen or C _1-4 alkyl; , 1 or 2 non-adjacent members of "b", "c", and "d" are optionally double bonds; and when R ₂ is hydrogen, "e" is a double bond or 16α. , 17α-epoxide, and when R ₂ is methylene, “e” is absent and “f” is a double bond]
Use of a compound represented by: 15. R ₁ is acetyl, R ₂ and R ₃ are hydrogen, and
a "," b "," c "and" d "are absent," e "is a double bond,
That is, the compound is estra-1,3,5 (10), 16-tetraen-3-yl
Use according to claim 14, which is acetate. 16. Use according to claim 14, wherein the increased alertness is manifested by an increased response to external stimuli, including alarm signals. 17. An expression of an effective amount for the vomeronasal organ of an individual: [Wherein R ₁ is hydrogen, C _1-5 alkanoyl, or —SO ₃ H or a salt thereof; R ₂ is hydrogen or methylene; R ₃ is hydrogen or C _1-4 alkyl; , 1 or 2 non-adjacent members of "b", "c", and "d" are optionally double bonds; and when R ₂ is hydrogen, "e" is a double bond or 16α. , 17α-epoxide, and when R ₂ is methylene, “e” is absent and “f” is a double bond]
A method of increasing alertness in an individual who does not have a medical condition that impairs alertness, comprising administering a compound represented by the formula: 18. The method of claim 17, wherein the administering comprises releasing the compound into the environment around the individual. 19. R ₁ is acetyl, R ₂ and R ₃ are hydrogen, and
a "," b "," c "and" d "are absent," e "is a double bond,
That is, the compound is estra-1,3,5 (10), 16-tetraen-3-yl
18. The method of claim 17, which is acetate. 20. The method of claim 17, wherein increased alertness is manifested by increased response to external stimuli, including alarm signals. 21. The method of claim 17, wherein the individual is a healthy individual.